Corticotropin releasing factor (CRF) is a primary co-ordinator of the body's response to stress through its endocrine and neurotransmitter actions. The effects of CRF are mediated by two receptor sub-types, CRF1 and CRF2. CRF antagonists may protect the brain during stroke since mixed CRF1/CRF2 peptide antagonists reduce ischemia-induced neuronal degeneration in animal models. In Phase studies we demonstrated that mRNA and peptide for CRF are elevated in the rodent brain following cerebral ischemia, and that CRF1 receptor antagonists are neuroprotective in animal stroke models. However, CRF may have protective effects through CRF2 receptors on cerebral blood vessels. Consequently, for neuroprotection, a CRF1 antagonist is the optimal approach. Neurocrine has identified novel small molecule, CRF1 receptor-selective antagonists which cross the blood-brain barrier after intravenous administration. A major goal of the Phase Il studies is to optimize a CRF1 receptor antagonist for advancement to clinical trials in stroke. Furthermore, a CRF1 receptor antagonist will be characterized in various animal models of stroke, to provide information which will guide the clinical studies. In addition, studies will be undertaken which are designed to elucidate the precise cellular mechanisms which give rise to CRF-induced neuronal degeneration and protection by CRF1 receptor antagonists. PROPOSED COMMERCIAL APPLICATION: According to the American Heart Association, stroke is the third leading cause of death in the U.S.A. with approximately 500,000 new cases each year and a total of 4 million affected individuals. It is the leading cause of serious long-term disability amongst Americans. The only currently approved therapy in the U.S.A. is the thrombolytic agent, tPA. Consequently, there is a large unmet medical need for effective drugs to reduced the devastating consequences of stroke on brain function. Neurocrine has exclusive rights from the Salk Institute to one issued patent to the cloned CRF1 receptor and its homologs, and Neurocrine owns an issued patent on the CRF2 receptor and its homologs. Neurocrine also has several patent applications in place for composition of matter protection on their small molecule CRF receptor antagonists. The proposed Phase II studies will identify a small molecule CRF1 selective antagonist suitable for acute intervention in stroke and provide a detailed characterization of its neuroprotective properties in animal models and its mechanism of action. This information will guide clinical studies designed to evaluate the safety and efficacy of such a compound in human stroke, and ultimately define the commercial application.